Symptom-related fears and associated hypervigilance toward disease-related stimuli (gastrointestinal [GI] sensations, symptoms or contexts) may play an important role in triggering central pain amplification systems in irritable bowel syndrome (IBS). This R03 tests the general hypothesis that central pain amplification in IBS is in part related to impairment in brain mechanisms responsible for regulating attention. Attention is a process involving the selection of competing sensory information to optimize current behavioral responses to specific stimuli relevant for the organism. I hypothesize that central pain amplification in IBS is related to impairment in attention processes responsible for filtering distracting information, i.e., symptom-related stimuli. I will test the specific hypothesis that decreased engagement of prefrontal cortical (PFC) control mechanisms will result in diminished PFC control over threat-related distracters and disinhibition of emotional arousal circuits (amygdala-centered pre-attentive threat mechanisms). Functional magnetic resonance imaging will be used to evaluate differences in the engagement of selective attention networks during emotional and threat-related stimuli in IBS patients versus healthy control subjects. Brain responses and behavioral performance on tasks indexing general attention (alerting, orienting, executive) and selective attention to disease-relevant GI words and threatening stimuli are compared between IBS and control subjects. To make valid causal inferences regarding the brain regions/networks and behavior, transcranial magnetic stimulation will be applied to produce temporary and fully reversible inactivation of the dorsolateral PFC in controls. The proposed studies are an extension of my K08 award that aims to identify the neuroanatomical substrates of the cognitive, behavioral, affective and physiologic alterations in IBS patients. This research will provide preliminary data for a planned R01 grant proposal focused on delineating the mechanism of PFC dysfunction in IBS. More complete understanding of cognitive mechanisms involved in central pain amplification will provide a better understanding of non-pharmacological treatment approaches such as cognitive behavioral therapy. PUBLIC HEALTH RELEVANCE: Irritable bowel syndrome is a common, chronic functional gastrointestinal disorder, characterized by abdominal pain and altered bowel habits, with significant impact on health-related quality of life and health care utilization. A better understanding of the biological mechanisms underlying central amplification of abdominal pain may increase progress in the development of more effective pharmacological therapies. The current research evaluates the attentional mechanisms and underlying brain circuits necessary to filter non-relevant information from the gut, and will test whether these functions are impaired in IBS.